ESR1 is co-expressed with closely adjacent uncharacterised genes spanning a breast cancer susceptibility locus at 6q25.1.
ESR1 is co-expressed with closely adjacent uncharacterised genes spanning a breast cancer susceptibility locus at 6q25.1.
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DOI：
10.1371/journal.pgen.1001382
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发表时间：
2011-04
期刊：
影响因子：
4.5
通讯作者：
Dowsett M
中科院分区：
文献类型：
--
作者：
Dunbier AK;Anderson H;Ghazoui Z;Lopez-Knowles E;Pancholi S;Ribas R;Drury S;Sidhu K;Leary A;Martin LA;Dowsett M
大约80%的人乳腺癌表现为雌激素受体α阳性（ER+ve）疾病，ER状态是治疗决策的关键因素。最近，6q25.1上ER基因（ESR 1）上游区域的单核苷酸多态性（SNP）与乳腺癌风险相关。我们对ER+ve肿瘤中与ESR 1表达水平相关的因素的研究揭示了该区域基因与ESR 1表达之间的意想不到的关联，这在乳腺癌风险遗传原因的研究中非常重要。在Illumina 48 K微阵列上分析了来自104名绝经后妇女在用芳香酶（雌激素合成酶）抑制剂治疗2周之前和之后的肿瘤活检的RNA。多重检验校正的斯皮尔曼相关性显示，位于ESR 1上游的三个先前未表征的开放阅读框架（ORF），C6 ORF 96，C6 ORF 97和C6 ORF 211与ESR 1高度相关（Rs分别为0.67，0.64和0.55，FDR<1×10−7）。 公开可用的数据集证实了其他ER+ve肿瘤组中的这种关系。DNA拷贝数的变化不能解释这种相关性。在培养的细胞中保持相关性。ERα拮抗剂不影响ORF的表达及其与ESR 1的相关性，表明它们的转录共激活不是由ERα直接介导的。siRNA抑制C6 ORF 211抑制MCF 7细胞的增殖，并且C6 ORF 211与肿瘤中的增殖元基因正相关。相反，C6 ORF 97表达与多基因呈负相关，并预测在他莫昔芬治疗的已发表数据集中无病生存率的改善，独立于ESR 1。我们的观察结果表明，以前归因于ER的一些生物学效应可以通过这些共表达基因介导和/或修饰。这些基因的共同表达和功能可能对最近发现的该区域SNP与乳腺癌风险之间的关系产生重要影响。最近的全基因组分析表明，基因在染色体上的排列方式和这些染色体的构象对基因表达的调控至关重要。为了反映这种排列，人们发现了一起受调控的基因簇。我们已经确定了一个以前未报告的转录活性枢纽跨越ESR 1，基因编码的重要乳腺癌生物标志物雌激素受体。最近，ESR 1上游的遗传变异与乳腺癌风险有关。我们发现，该区域内的三个开放阅读框与ESR 1紧密共表达。我们研究了这些基因的功能，发现其中一个共表达基因C6 ORF 211影响培养细胞的增殖，并与乳腺肿瘤的增殖相关。另一个基因C6 ORF 97与乳腺肿瘤的增殖呈负相关，并预测抗雌激素药物他莫昔芬的结果。这些发现表明，这些基因可能有助于与雌激素受体阳性相关的表型。此外，它们可能参与基因组该区域的遗传变异导致乳腺癌易感性的机制。
Approximately 80% of human breast carcinomas present as oestrogen receptor α-positive (ER+ve) disease, and ER status is a critical factor in treatment decision-making. Recently, single nucleotide polymorphisms (SNPs) in the region immediately upstream of the ER gene (ESR1) on 6q25.1 have been associated with breast cancer risk. Our investigation of factors associated with the level of expression of ESR1 in ER+ve tumours has revealed unexpected associations between genes in this region and ESR1 expression that are important to consider in studies of the genetic causes of breast cancer risk. RNA from tumour biopsies taken from 104 postmenopausal women before and after 2 weeks treatment with an aromatase (oestrogen synthase) inhibitor was analyzed on Illumina 48K microarrays. Multiple-testing corrected Spearman correlation revealed that three previously uncharacterized open reading frames (ORFs) located immediately upstream of ESR1, C6ORF96, C6ORF97, and C6ORF211 were highly correlated with ESR1 (Rs = 0.67, 0.64, and 0.55 respectively, FDR<1×10−7). Publicly available datasets confirmed this relationship in other groups of ER+ve tumours. DNA copy number changes did not account for the correlations. The correlations were maintained in cultured cells. An ERα antagonist did not affect the ORFs' expression or their correlation with ESR1, suggesting their transcriptional co-activation is not directly mediated by ERα. siRNA inhibition of C6ORF211 suppressed proliferation in MCF7 cells, and C6ORF211 positively correlated with a proliferation metagene in tumours. In contrast, C6ORF97 expression correlated negatively with the metagene and predicted for improved disease-free survival in a tamoxifen-treated published dataset, independently of ESR1. Our observations suggest that some of the biological effects previously attributed to ER could be mediated and/or modified by these co-expressed genes. The co-expression and function of these genes may be important influences on the recently identified relationship between SNPs in this region and breast cancer risk. Recent genome-wide analysis has revealed that the way in which genes are arranged on chromosomes and the conformation of these chromosomes are crucial for the regulation of gene expression. Reflecting this arrangement, clusters of genes which are regulated together have been discovered. We have identified a previously unreported transcriptional activity hub spanning ESR1, the gene encoding the important breast cancer biomarker oestrogen receptor. Genetic variants immediately upstream of ESR1 have recently been linked to breast cancer risk. We found that three open reading frames within this region are tightly co-expressed with ESR1. We investigated the function of these genes and discovered that one of these co-expressed genes, C6ORF211, affects proliferation in cultured cells and is correlated with proliferation in breast tumours. Another of the genes, C6ORF97, is negatively correlated with proliferation in breast tumours and predicts for outcome on the anti-oestrogen drug tamoxifen. These findings suggest that the genes could contribute to the phenotype associated with oestrogen-receptor positivity. In addition, they may be involved in the mechanism by which genetic variation in this region of the genome contributes to breast cancer susceptibility.
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